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Polymorphism in the Thymidylate Synthase Promoter Enhancer Region and Risk of Colorectal Adenomas

Departments of ¹ Community and Preventive Medicine and ² Microbiology, Mount Sinai School of Medicine, New York, New York; ³ Department of Adult Oncology, Dana-Farber Cancer Institute; ⁴ Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; and ⁵ Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts

Requests for reprints: Jia Chen, Department of Community and Preventive Medicine, Box 1043, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Phone: 212-241-7519; Fax: 212-360-6965. E-mail: jia.chen{at}mssm.edu

Thymidylate synthase (TS), a key one-carbon metabolizing gene, encodes an enzyme that converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. We recently reported that a promoter polymorphism in TS modified the risk of colorectal cancer as well as the survival rate after the disease. To explore whether TS may play an important role in colorectal carcinogenesis early in the multistaged pathogenic pathway, we investigated the relation between the TS promoter polymorphism and risk of colorectal adenoma in a nested case-control study within the prospective Health Professionals Follow-up Study. We ascertained the TS genotype from 373 incident colorectal adenoma cases and 720 control subjects. Although there was no overall association between the TS promoter polymorphism and adenoma risk, we observed a significant TS-alcohol interaction (P for interaction = 0.009); relative to low alcohol consumers with the 2R/2R genotype, those with high alcohol consumption (>30 g/d) were not at elevated risk if they had the 2R/2R genotype [relative risk (RR), 0.80; 95% confidence interval (95% CI), 0.34-1.90], but were at higher risk if they had the 2R/3R genotype (RR, 1.70; 95% CI, 0.87-3.31), and at the highest risk (RR, 3.16; 95% CI, 1.50-6.63) if they had the 3R/3R genotype. In addition, a significant interaction was observed between the TS promoter polymorphism and the 677C > T polymorphism of methylenetetrahydrofolate reductase (MTHFR; P for interaction = 0.007). These findings lend additional support that one-carbon metabolism is an important process in pathogenesis of colorectal cancer.

Key Words: colorectal cancer • colorectal adenoma • thymidylate synthase • one-carbon metabolism • folate

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